Immunologic resilience and COVID-19 survival advantage - 04/11/21
South Texas Veterans Health Care System COVID-19 Teamd, ‡, ¶
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Abstract |
Background |
The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR).
Objective |
We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality.
Methods |
IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non–COVID-19 cohorts (n = 13,461) provided the framework for linking pre–COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes.
Results |
IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non–COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females.
Conclusions |
Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Aging, AIDS, biomarkers, COVID-19, HIV, immune, inflammation, influenza, SARS-CoV-2
Abbreviations used : CMV, COVID-19, FHS, GO-BP, HR, IC, IF, IHG, IQR, IR, N, OR, RR, SARS-CoV-2, SLE
Plan
| The main sources of funding for the data presented herein are those awarded to S.K.A., M.I.R., and J.F.O. S.K.A. was supported by grants from the Veterans Affairs (VA) (VA Center for Personalized Medicine, grant no. IP1 CX000875-01A1), by the National Institutes of Health (NIH) MERIT award (grant no. R37AI046326), by the Doris Duke Distinguished Clinical Scientist Award, by the Burroughs Wellcome Clinical Scientist Award in Translational Research, and by the Elizabeth Glaser Pediatric AIDS Foundation. The work was also supported, in part, by an award jointly funded by the National Institute of Allergy and Infectious Diseases (NIAID)/NIH (grant no. AAI20042-001) and the Department of Veterans Affairs (grant no. COVID19-8100-01) awarded to S.K.A. and M.I.R. A portion of the material presented is based on research sponsored by the US Air Force under agreement number FA8650-17-2-6816 (US Air Force 59th Medical Wing Intramural Award to J.F.O.). The HIV cohort was supported by the Infectious Disease Clinical Research Program (grant no. IDCRP-000-03), a Department of Defense program executed by the Uniformed Services University of the Health Sciences through a cooperative agreement with The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The latter project has been supported with federal funds from the NIAID/NIH (under Inter-Agency Agreement no. Y1-AI-5072) and from the Defense Health Program, US Department of Defense (under award no. HU0001190002). The SardiNIA study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (with contract nos. N01-AG-1-2109 and HHSN271201100005C); by Italian grants (grant no. FISM 2011/R/13, grant no. FaReBio2011, Funds MIUR/CNR for Rare Diseases and Molecular Screening, CNR/DSB flagship INTEROMICS, PNR/CNR Aging Program 2012-2014); European Union’s Horizon 2020 Research and Innovation Programme (under grant agreement no. 633964); Giovani Ricercatori 2007 (D.lgs 502/92); and Legge Regionale 30 giugno 2011 n.12, articolo 3, comma 3 (FC). G.C.L. was supported by the NIH (grant no. K23-AG066933). A.M.S. was supported by the NIH (grant no. T32DE014318 COSTAR) institutional research training grant. This work was also supported by pilot project funding to S.K.A. (from 1UL1 TR002645 Clinical and Translational Science Award, San Antonio Claude D. Pepper Older Americans Independence Center grant no. P30 AG044271, and Long School of Medicine, UTHSCA). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. The views expressed are those of the authors and do not reflect the official views of the Uniformed Services University of the Health Sciences, the National Institutes of Health, or the Department of Health and Human Services, the Department of Defense, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US government. The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46. The US government is authorized to reproduce and distribute reprints for governmental purposes notwithstanding any copyright notation thereon. |
Vol 148 - N° 5
P. 1176-1191 - novembre 2021 Retour au numéro
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